23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      A Study of Potential Pharmacokinetic and Pharmacodynamic Interactions between Dextromethorphan/Quinidine and Memantine in Healthy Volunteers

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background and Objective: Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist.

          Methods: This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30mg (dextromethorphan 30mg/quinidine 30mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan — the dextromethorphan metabolite — and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed.

          Results: A total of 52 subjects were randomized. In both group 1 (n=23) and group 2 (n=29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8–1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic variables were either similar or slightly improved with DMQ added to memantine and memantine added to DMQ, compared to monotherapy with either agent.

          Conclusion: Minimal pharmacokinetic and pharmacodynamic interactions were observed between memantine and DMQ, suggesting they can be coadministered without dose adjustment.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: not found

          Open-loop and closed-loop control of posture: a random-walk analysis of center-of-pressure trajectories.

          A new conceptual and theoretical framework for studying the human postural control system is introduced. Mathematical techniques from statistical mechanics are developed and applied to the analysis and interpretation of stabilograms. This work was based on the assumption that the act of maintaining an erect posture could be viewed, in part, as a stochastic process. Twenty-five healthy young subjects were studied under quite-standing conditions. Center-of-pressure (COP) trajectories were analyzed as one-dimensional and two-dimensional random walks. This novel approach led to the extraction of repeatable, physiologically meaningful parameters from stabilograms. It is shown that although individual stabilograms for a single subject were highly variable and random in appearance, a consistent, subject-specific pattern emerged with the generation of averaged stabilogram-diffusion plots (mean square COP displacement vs time interval). In addition, significant inter-subject differences were found in the calculated results. This suggests that the steady-state behavior of the control mechanisms involved in maintaining erect posture can be quite variable even amongst a population of age-matched, anthropometrically similar, healthy individuals. These posturographic analyses also demonstrated that COP trajectories could be modelled as fractional Brownian motion and that at least two control systems-a short-term mechanism and a long-term mechanism-were operating during quit standing. More specifically, the present results suggest that over short-term intervals open-loop control schemes are utilized by the postural control system, whereas over long-term intervals closed-loop control mechanisms are called into play. This work strongly supports the position that much can be learned about the functional organization of the postural control system by studying the steady-state behavior of the human body during periods of undisturbed stance.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.

            Patients with ALS commonly exhibit pseudobulbar affect. The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis.

              To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients. A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale. Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p
                Bookmark

                Author and article information

                Contributors
                Lpope@avanir.com
                Journal
                Clin Drug Investig
                Clin Drug Investig
                Clinical Drug Investigation
                Springer International Publishing (Cham )
                1173-2563
                1179-1918
                13 December 2012
                13 December 2012
                August 2012
                : 32
                : 8
                : e1-e15
                Affiliations
                [ ]Clinical Research, Avanir Pharmaceuticals, Inc., 20 Enterprise, Suite 200, Aliso Viejo, California CA 92656 USA
                [ ]INC Research — Toronto, Toronto, Canada
                [ ]DL Global Partners Inc., Toronto, Canada
                Article
                1905
                10.1007/BF03261905
                3714141
                22712629
                2a0a4656-1c51-4df0-a0d6-b6a933fe354c
                © Springer International Publishing AG 2012
                History
                Categories
                Original Research Article
                Custom metadata
                © Springer International Publishing AG 2012

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

                Comments

                Comment on this article